Management of spinal giant cell tumors

The Spine Journal 16 (2016) 259–269

Review Article

Management of spinal giant cell tumors Panya Luksanapruksa, MDa, Jacob M. Buchowski, MD, MSb,*, Weerasak Singhatanadgige, MD, MSc, Peter C. Rose, MDd, David B. Bumpass, MDb a

Department of Orthopedic Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Rd, Bangkoknoi, Bangkok 10700, Thailand b Department of Orthopaedic Surgery, Washington University in St. Louis, 425 South Euclid Ave., St. Louis, MO 63110, USA c Department of Orthopedics, Faculty of Medicine, Chulalongkorn University; King Chulalongkorn Memorial Hospital, Thai Red Cross Society, 1873, Rama IV Road, Pathumwan, Bangkok 10330, Thailand d Department of Orthopedic Surgery, Mayo Clinic, 200 First St. SW, Gonda 14S, Rochester, MN 55905, USA Received 1 June 2015; revised 9 October 2015; accepted 22 October 2015

Abstract

BACKGROUND CONTEXT: Spinal giant cell tumors (SGCT) remain challenging tumors to treat. Although advancements in surgical techniques and adjuvant therapies have provided new options for treatment, evidence-based algorithms are lacking. PURPOSE: This study aims to review the peer-reviewed literature that addresses current treatment options and management of SGCT, to produce an evidence-based treatment algorithm. STUDY DESIGN/SETTING: A systematic review was performed. METHODS: Articles published between January 1, 1970 and March 31, 2015 were selected from PubMed and EMBASE searches using keywords “giant cell tumor” AND “spine” AND “treatment.” Relevant articles were selected by the authors and reviewed. RESULTS: A total of 515 studies were identified, of which 81 studies were included. Complete surgical resections of SCGT resulted in the lowest recurrence rates. However, morbidity of en bloc resections is high and in some cases, surgery is not possible. Intralesional resection can be coupled with adjuvant therapies, but evidence-based algorithms for use of adjuvants remain elusive. Several recent advancements in adjuvant therapy may hold promise for decreasing SGCT recurrence, specifically stereotactic radiotherapy, selective arterial embolization, and medical therapy using denosumab and interferon. CONCLUSIONS: Complete surgical resection of SGCT should be the goal when possible, particularly if neurologic impairment is present. Denosumab holds promise as an adjuvant and perhaps stand-alone therapy for SGCT. Spinal giant cell tumors should be approached as a case-by-case problem, as each presents unique challenges. Collaboration of spine surgeons, radiation oncologists, and medical oncologists is the best practice for treating these difficult tumors. © 2015 Elsevier Inc. All rights reserved.

Keywords:

Adjuvant therapy; Denosumab; Giant cell tumor; Mobile spine; Sacrum; Spine tumor

FDA device/drug status: Not applicable. Author disclosures: PL: Nothing to disclose. JMB: Consulting: Advance Medical (Personal Fees (F)), Corelink, Inc (Personal Fees (B)), Globus Medical, Inc (Personal Fees (C)), K2M, Inc (Personal Fees (B)), Medtronic, Inc (Personal Fees (D)), Stryker, Inc (Personal Fees (C)); Teaching: Broadwater/Vertical Health (Personal Fees (B)), DePuy Synthes (Personal Fees (C)), Globus Medical, Inc, (Personal Fees (B)), Orthofix (Personal Fees (C)), Stryker, Inc (Personal Fees (C)); Royalties: Wolters Kluwer Health, Inc (Personal Fees (B)), Globus Medical, Inc (Personal Fees (D)); Expert Testimonies: Various entities (Personal Fees (F)); Other, Teaching, Not-forProfit Organization: AO Foundation (Parent organization to AO Spine) (Nonhttp://dx.doi.org/10.1016/j.spinee.2015.10.045 1529-9430/© 2015 Elsevier Inc. All rights reserved.

Financial Support (B)), outside the submitted work. WS: Nothing to disclose. PCR: Nothing to disclose. DBB: Nothing to disclose. The disclosure key can be found on the Table of Contents and at www.TheSpineJournalOnline.com. No funds were received in support of this work. There are no relevant financial activities outside the submitted work. * Corresponding author. Department of Orthopaedic Surgery, Washington University in St. Louis, 425 South Euclid Ave., St. Louis, MO 63110, USA. Tel.: +1 314 747 4950; fax: +1 314 747 2599. E-mail address: [email protected] (J.M. Buchowski)

260

P. Luksanapruksa et al. / The Spine Journal 16 (2016) 259–269

Introduction Spinal giant cell tumors (SGCTs) are a locally aggressive benign bone tumor that can occur anywhere along the spine. Goals of SGCT treatment are tumor removal, spinal stability, and neural tissue decompression. Choices of treatment are en bloc vertebrectomy and intralesional resection. Because of the proximity of vital structures to the vertebrae, en bloc resection may be too damaging to undertake in some cases. Therefore, intralesional curettage might be the alternative choice in selected cases. Numerous adjuvant therapies can be used with either of these two surgical strategies. The objective of this article was to review the peerreviewed literature that addresses current treatment options and management of SGCT to produce an evidence-based treatment algorithm. Methods Two independent reviewers (PL, WS) performed a search of the all peer-reviewed relevant literatures in English published between January 1, 1970 and March 31, 2015. Electronic database queries including EMBASE and PubMed were searched using keywords “giant cell tumor” AND “spine” AND “treatment”. Additional searches were performed by using reference lists of the retrieved studies that were relevant to SGCT. Inclusion criteria were studies describing biology, evaluation, and treatment of SGCT. Exclusion criteria were review articles. According to PRISMA flow diagram, both reviewers independently screened abstracts and titles after removing duplicate publications. Then, thorough full-paper readings were performed of the studies that might meet the inclusion criteria to determine final inclusion. Disagreements were solved by discussion for consensus. Results There were 752 publications identified through database searching (420 PubMed, 332 EMBASE) and 237 publications were found in both search methods; thus, a total of 515 unique abstracts were screened. Of these abstracts, 142 were

selected for full paper review; 81 of these articles were included. Levels of evidence were classified as shown in Table 1. Epidemiology and presentation Giant cell tumors (GCTs) are locally aggressive benign bone tumors. Approximately 5% of all primary bone tumors are GCTs. The prevalence of spinal giant cell tumors (SGCTs) is estimated at 2%–15% of all GCTs; incidence is higher in the sacral region and in patients aged 20–40 years [1–6]. Some studies have also reported that SGCTs are more common in female patients [1,2,7,8]. Spinal giant cell tumor patients typically present with pain, and up to 72% of patients also experience neurologic deficits such as radicular pain and motor weakness from nerve root or spinal cord compression [2–4,9–11]. A palpable mass is only rarely appreciated [2]. Although GCTs are generally benign tumors, they can be locally aggressive and can cause considerable osseous destruction and soft tissue extension, often leading to neurologic compromise in the spine. Spinal giant cell tumors have an overall survival rate of 93% [12]. However, GCTs can undergo malignant transformation, hematogenously metastasizing most frequently to the lungs [5,13–15]. However, Tubbs et al. reported that the prevalence of lung metastases in a benign GCT was 3% (13 of 475) [16]. Donthineni et al. reported that 14% of SGCT patients developed lung metastases, suggesting a higher rate of metastasis than the 1%–6% rate reported for extremity GCTs [13,15,17]. A very small fraction of GCTs (2%) undergo sarcomatous change, most often to osteosarcoma. This can occur as a primary malignant GCT or, more commonly, as a secondary malignancy after radiation therapy (RT) of a benign GCT [6]. Radiographic and pathologic diagnosis The radiographic appearance of spinal GCTs is typically an osteolytic, expansile lesion with significant cortical destruction. Often there is a “soap bubble” pattern and an absence of a sclerotic border. In the spine, GCTs typically involve the vertebral body, and can extend into the posterior elements and paraspinal tissues. Adjacent disks and vertebrae can be involved as well, and pathologic compression fractures are

Table 1 Levels of evidence for primary research question adopted by the North American Spine Society, January 2005 Level

Description

I

High-quality randomized trial or prospective study; testing of previously developed diagnostic criteria on consecutive patients; sensible costs and alternatives; values obtained from many studies with multiway sensitivity analyses; systematic review of Level I randomized controlled trials (RCTs) and Level I studies. Lesser quality RCT; prospective comparative study; retrospective study; untreated controls from an RCT; lesser quality prospective study; development of diagnostic criteria on consecutive patients; sensible costs and alternatives; values obtained from limited studies; with multiway sensitivity analyses; systematic review of Level II studies or Level I studies with inconsistent results. Case control study (therapeutic and prognostic studies); retrospective comparative study; study of non-consecutive patients without consistently applied reference “gold” standard; analyses based on limited alternatives and costs and poor estimates; systematic review of Level III studies. Case series; case control study (diagnostic studies); poor reference standard; analyses with no sensitivity analyses. Expert opinion

II

III IV V

P. Luksanapruksa et al. / The Spine Journal 16 (2016) 259–269

261

Fig. 1. Magnetic resonance imaging (MRI) of the lumbar spine demonstrates similar low-to-moderate intensity on both T1- (Left) and T2-weighted (Right) MRI at the L5 level.

common. More than 90% of GCTs demonstrate similar lowto-moderate intensity on both T1- and T2-weighted magnetic resonance imaging (Fig. 1). There may also be fluid-fluid levels seen on imaging, giving an appearance of coexisting aneurysmal bone cysts [1,2,18–20]. Pathologic analysis of GCTs demonstrates osteoclastlike giant cells surrounded with mononuclear cells that contain vesicular nuclei. Matrix mineralization is notably absent, and hemorrhagic areas are often seen as well (Fig. 2) [18]. It is important to remember that ultimate prognosis for GCTs has not been found to correlate consistently with histologic grading [9,17,21–24]. The differential diagnosis for SGCT includes

aneurysmal bone cyst, metastatic tumor, osteoblastoma, osteitis fibrosa cystica from hypoparathyroidism, lymphoma, chordoma, and malignant fibrous histiocytoma [8,18]. The most useful staging system for SGCTs is the WeinsteinBoriani-Biagini (WBB) system. The WBB system communicates information regarding the extent and anatomic position of the SGCT within the spinal column and has been shown to be very useful in planning resection approaches [2]. The Enneking system has usefulness for SCGTs as well. In this classification, benign lesions are staged as 1, 2, or 3. Most GCTs are either stage 2 (cortical thinning, sclerotic rim, soft tissue pseudocapsule) or stage 3 (cortical breakthrough, soft-tissue mass) [5,25]. Surgical decision making

Fig. 2. Pathologic study of giant cell tumors (GCTs) demonstrates osteoclastlike giant cells surrounded with mononuclear cells that contain vesicular nuclei. Matrix mineralization is notably absent.

Surgery is the mainstay of treatment for SGCTs [6]. The goals of any SGCT resection are to remove as much tumor as possible, decompress the neural elements, and stabilize the spine. The literature as a whole does seem to support that complete resection of SGCTs with disease-free margins results in a lower recurrence rate and increased disease-free survival than intralesional resection, although no definitive systematic review of this topic has been done [2,5,10,12,17,26–28] (Level of evidence: III–IV). However, en bloc excision in the spine has significant risk of postoperative neurologic deficit, especially in the cervical spine [27,29]. Thus, plans for surgical treatment of SGCTs must weigh neurologic risk against complete tumor excision, a difficult balance to strike. Hart et al. reported that referral to a tertiary hospital before attempted SGCT resection resulted in a notably lower recurrence rate (18%) than patients whose resections were attempted

262

P. Luksanapruksa et al. / The Spine Journal 16 (2016) 259–269

at smaller hospitals (83%) (Level of evidence: III) [2]. Both biopsy and resection of SGCTs should be performed in the same tertiary center, to allow for effective communication between radiologists, pathologists, and surgeons in planning resection and minimizing unnecessary or repeat procedures for the patient. Moreover, surgical resection in Xu et al. presented a retrospective analysis of 102 SGCT patients; all lesions were in the mobile spine. They found that total spondylectomy (either en bloc resection or a piecemeal complete resection) predicted a lower risk of recurrence (hazard ratio 2.6, p=.05). Patients who had resections before age 40 also had better recurrence prognosis, with a hazard ratio of 4.1 (p<.01) [12]. Junming et al. treated a series of 22 cervical SGCT patients; 14 patients underwent complete tumor removal via piecemeal resection, and 8 patients underwent subtotal resection. Eighteen of the patients also received postoperative RT (30–50 Gy). Tumor recurred in 71% of the patients who had subtotal resections but in only 8% of patients with complete resections [10]. Martin and McCarthy reported outcomes of 23 SGCT patients, 13 of which were in the mobile spine (spine above the sacrum). Eleven of these patients were treated with en bloc resection, with two (18%) developing recurrences; the other two patients were treated with intralesional surgical resection and both developed recurrent GCTs (100%) [27]. In an attempt to better predict which SGCTs are more likely to recur, Boriani et al. classified 49 SGCTs by Enneking grade. They found that Enneking stage 2 tumors treated with intralesional curettage did not recur in 94% of cases. However, Enneking stage 3 tumors treated with intralesional resection recurred in 61% of cases by 5 years’ follow-up, whereas en bloc resection of these lesions resulted in 90% recurrencefree control after 5 years (p=.01) [5]. Sacral GCTs are a subset of the SGCT population that pose unique challenges for resection and reconstruction, as these are often large tumors. Definitive treatment guidelines for sacral GCTs have not been established. In their SGCT series, Martin et al. had 10 sacral GCT patients. Two of the sacral GCT patients had en bloc resections, with neither developing a recurrence (0%). Six sacral GCT patients were treated with preoperative arterial embolization and intralesional surgical resection, and 2 (33%) developed a recurrence. One sacral GCT patient was treated only with serial arterial embolization with good disease control. Leggon et al. reported 10 sacral GCT cases and combined these cases with those gleaned from a literature review for a total of 166 lesions. They concluded that sacral GCTs had an overall recurrence rate of 48%, but that no patients with wide excisions experienced recurrence [30]. Li et al. reported on treatment of 32 sacral GCT patients who were treated with wide resection (N=2), marginal resection (N=11), marginal resection plus curettage (N=12), or curettage alone (N=7). All patients underwent preoperative embolization. Twelve patients (37.5%) experienced local recurrence, with the marginal resection group having a significantly lower risk of recurrence than the curettage group

(18% vs. 71%, respectively; p=.05). These authors concluded that curettage alone should not be used to treat sacral GCTs [31]. Conversely Guo et al. treated 24 sacral GCT more conservatively with intralesional curettage or partial excision. The median follow-up duration was 50 months (range: 25–132 months). Seven (29.2%) patients developed radiological recurrence. The mean time from the index surgical procedure to the first recurrence was 13 months (range: 8–31 months). The 5-year local recurrence rate was 20.4% (Level of evidence: IV) [32]. Surgical techniques Choice of surgical approach for SGCT resection should incorporate WBB tumor staging to identify how best to safely deliver the tumor from around the spinal cord [2]. Typically either an anterior and posterior combined approach or a posterior-only approach is used; the combined approach is necessary if there is significant anterior soft tissue extension near vital structures. Recent technology advances can assist with these difficult resections. Several studies have reported the usefulness of computer-aided surgical navigation for en bloc SGCT resections in the thoracic spine [33,34]. Yamazaki et al. created a three-dimensional printed full-scale model of a cervical GCT that was useful for preoperative planning, particularly by demonstrating the course of the vertebral artery relative to the tumor [35]. A number of reconstruction techniques after tumor removal have been described. Anterior column reconstruction can be achieved with expandable cages. Segmental instrumentation is placed above and below the resection for stability; instrumentation can be anterior, posterior, or combined [7]. Shimada et al. used these techniques in two cases of L5 GCT reconstruction, which were particularly challenging given that the tumor’s location at the lumbosacral junction provided limited distal fixation [11]. Samartzis et al. used a combined anterior and posterior surgical approach to resect a lumbar GCT via lumbar spondylectomy. Short-segment threecolumn reconstruction was achieved using an anterior cage device with connectors to the posterior rods to function as pedicle reconstruction. At 33 months post surgery, the tumor had not recurred, and the patient was neurologically intact and active [36]. Sacral GCTs typically require an anterior approach, and if instrumentation is needed to restore stability, then a posterior approach is performed as well. The exploration of large sacral GCTs via a posterior approach alone may be unsuccessful because of both extensive bleeding and difficult accessibility. Consideration of the location and size of the tumor guides decision making regarding resection technique. Li et al. managed 32 sacral GCT patients using an algorithmic approach: S3–S5 tumors underwent en bloc resection; midline tumors underwent proximal curettage (S1–S2 segments) and distal marginal resection (S3–S5 segments); and eccentric proximal tumors underwent marginal resection

P. Luksanapruksa et al. / The Spine Journal 16 (2016) 259–269

263

include radiation, selective arterial embolization (SAE), cryotherapy, ABC, and medications such as bisphosphonates, denosumab, and interferon alpha (Table 1). However, highlevel evidence for the effectiveness of these adjuvant therapies is lacking. A summary of the best level of evidence of adjuvant therapies is shown in Table 2. Few studies have been performed to develop an algorithm for appropriate use of these treatments [39]. The treatment algorithm for SGCTs is shown in Fig. 3.

with preservation of all contralateral nerve roots. Curettage was supplemented with adjuvant ethanol application or argon beam coagulation (ABC) using iodine-125 (Level of evidence: III) [31]. Preservation of both S3 nerve roots almost never leads to bowel or bladder incontinence, although unilateral S3 root sacrifice can result in partial incontinence in 30%–50% of patients (Level of evidence: IV) [32]. Soft tissue flap reconstruction may be necessary after some extensive sacral GCT resections [37]. Intraoperative complications in SGCT resections are not uncommon. Guo et al. noted a 41% complication rate in surgical treatment of 24 sacral GCT patients; 29% of the patients had a wound complication. Martin and McCarthy reported two cervical GCT patients who sustained vertebral artery injuries requiring ligation during resection, but fortunately, neither experienced postoperative deficits [27]. Shimada et al. reported massive bleeding from the iliolumbar vein when performing anterior resection of an L5 GCT, with nearly 7 L of blood loss [11]. Junming et al. noted a cerebrospinal fluid leak from the wound after total resection of a cervical GCT; the patient developed meningitis, which resolved after antibiotic treatment and wound debridement [10]. Because of the complex nature and high complication risk of SGCT resections, these operations should only be undertaken at centers with experienced multi-specialty surgical teams [38].

Radiation therapy Data on the effectiveness of RT for SGCT are conflicting, with some studies showing effectiveness and others suggesting that RT does not reduce GCT recurrence as either an adjuvant or stand-alone treatment in patients who cannot undergo surgery due to severe comorbidities or inoperable tumors [3]. Khan et al. reported six patients with SGCTS who were treated with subtotal tumor resection and radiotherapy (30–54 Gy). Mean follow-up was 13 years; five of six patients were alive with no evidence of disease, and one was alive with clinically asymptomatic disease [40]. Sharma et al. treated six patients with cervical SGCTs using subtotal resection and postoperative RT, and no patient had recurrence at a mean follow-up of 2 years [29]. Chakravarti et al. reported on 20 GCT patients, 12 with SGCT, who were managed with megavoltage radiation (10–160 MeV, 40–70 Gy). Of the 12 SGCT patients, 8 had undergone partial resection and 4 had no surgery. After a median follow-up of 9 years, tumors had not progressed in 17 of the 20 patients (85%). No radiation-induced malignant tumors were observed [41].

Adjuvant treatments Because complete resection of SGCT lesions remains a challenging surgical problem, a number of adjuvant therapies have been used to reduce the rate of recurrence. These Table 2 Summary of adjuvant therapies for spinal giant cell tumors (SGCTs) Therapy Radiotherapy

Selective arterial embolization

Argon beam coagulation Cryotherapy Bisphosphonates

Denosumab

Interferon alpha-2b

Indications • Recurrent SGCTs • Incomplete tumor resection • Inoperable tumors (due to risk or anatomic location) • Patients unable to undergo surgery due to medical comorbidities • Reduce operative blood loss • Primary treatment for inoperable or high-risk SGCTs Intraoperative adjuvant modality for intralesional resections Intraoperative adjuvant for intralesional resections • Adjuvant therapy after surgical resection • Primary treatment for inoperable or high-risk SGCTs • Adjuvant therapy after surgical resection • Primary treatment for inoperable or high-risk SGCTs Recurrent SGCTs

SGCTs, Spinal Giant cell tumors.

Modalities

Complications

Best level of evidence

• External beam (megavoltage) • Intensity-modulated radiotherapy • Stereotactic body radiotherapy (not yet reported)

Radiation-induced sarcoma

IV

• • • •

Spinal cord infarct

III

Gelfoam Polymer microspheres Coils Polyvinyl alcohol

IV

• Zolendronate • Ibandronate

Cold damage to neural elements • Subtrochanteric femur fracture • Jaw necrosis • Jaw necrosis • Hypocalcemia • Hypophosphatemia

III IV

II

IV

264

P. Luksanapruksa et al. / The Spine Journal 16 (2016) 259–269

Fig. 3. Treatment algorithm for spinal giant cell tumors.

However, Xu et al. performed a multivariate analysis of 102 SGCT patients, finding that adjuvant RT with surgery did not improve recurrence rates at either 2 years (p=.25) or 5 years (p=.25) after treatment [12]. In a literature review of 239 sacral and pelvic GCTs, Leggon et al. found that larger radiation doses (>55 Gy) achieved no significant reduction in recurrence rates over doses <45 Gy (p=.98). When the authors sub-analyzed only sacral GCTs (166 cases), treatment with intralesional resection and adjuvant RT achieved no improvement in recurrence rate compared with either RT alone or intralesional resection alone [30]. Ruggieri et al. reviewed 31 sacral GCT patients who underwent intralesional resection; use of adjuvant RT had no effect on recurrence [39]. Advances in RT technology may improve effectiveness for SGCTs. Roeder et al. used intensity-modulated radiotherapy

(IMRT) for treating GCTs not amenable to complete resection. Intensity-modulated radiotherapy uses advanced reconstructive imaging to deliver optimal radiation doses to irregularly shaped targets safely, with low dose exposure to surrounding structures. Five GCT patients (four sacral and one sphenoid sinus) were treated with IMRT to a median total dose of 64 Gy (range 58–66 Gy) in conventional fractions. After median follow-up of 46 months, the local control rate was 80% and overall survival was 100% [42]. Stereotactic body radiation therapy is a newer technique that has proved useful for malignant spinal tumors, but no reports exist for its use in treating SGCTs. The primary risk of using RT for SGCTs is causing radiation-induced sarcoma, typically osteosarcoma. These sarcomas are often aggressive. Leggon et al. reported that 11%

P. Luksanapruksa et al. / The Spine Journal 16 (2016) 259–269

of patients who received radiation for sacral or pelvic GCTs developed radiation-induced sarcomas; these malignancies were diagnosed at a mean 9.1 years after GCT RT. For this reason, RT for SGCT should be reserved for situations with no viable surgical or alternative adjuvant options. Two studies have also noted that adjuvant RT in excess of a total dose of 40 Gy places patients at risk of primary sarcomatous transformation of the GCT (Level of evidence: IV) [2,17].

265

symptoms at last follow-up (39–141 months). Diminished vascularity, stabilization of tumor size, and reossification were seen on imaging [50]. Although SAE is considered a relatively safe procedure, complications can occur. Finstein et al. reported a patient who developed a T12 paraplegia as a result of preoperative embolization for a thoracolumbar SGCT. At 6 months’ followup, the patient was disease-free but remained paralyzed below T12 [51].

Selective arterial embolization Surgical treatment of GCT frequently leads to significant operative blood loss. Preoperative SAE of SGCTs can reduce intraoperative blood loss, particularly for intralesional curettage. Zhou et al. reported that preoperative embolization of 28 patients with GCTs of the spine and sacrum followed by intralesional resection achieved local control [43]. The average intraoperative blood loss was 1,529 mL (range: 400– 5,800 mL), notably lower than previously reported mean blood loss for similar operations (2,400–20,000 mL) [44–46]. Hart et al. reported five SGCT patients who underwent preoperative embolization and then intralesional curettage; none of the patients (0%) developed a subsequent recurrence [2]. Ming et al. performed preoperative SAE along with intralesional resection for 28 SCGT patients. Local recurrence occurred in 47% of patients with tumors that extended beyond the vertebral compartment (Enneking grade 3), but in only 8% of patients without extension (Enneking grade 2); this was a significant difference (p<.05). These authors concluded that use of SAE and intralesional resection is likely not sufficient for extracompartmental SGCTs, and more extensive therapy should thus be considered in such cases [47]. Serial SAE has also been utilized as a stand-alone treatment for SGCTs deemed inoperable or with a high risk of neurologic injury. Lin et al. reported a series of 18 sacral GCT patients treated solely with SAE using gelfoam particles. Fourteen patients (78%) responded favorably to embolization, with improvement in pain and neurologic symptoms. Patients were embolized every 2–4 months until their clinical and radiographic presentation improved and the tumor was no longer hypervascular. Radiographic follow-up demonstrated sacral reossification and stabilization of tumor size at a median follow-up of 105 months [48]. Hosalkar et al. also reported nine patients with sacral GCTs who received initial primary treatment with serial SAE using stainless steel coils, gelfoam particles, and polyvinyl alcohol. All patients underwent SAE at the time of diagnosis, followed by repeat embolization every 6 weeks until no new vessels were noted, and then again at 6 and 18 months following stabilization of the lesion. No progression was noted in 7 of the 9 cases (78%). Two cases experienced tumor progression of less than 1 cm early in the treatment course but continued to remain asymptomatic. All patients showed substantial pain relief [49]. Similarly, Nakanishi et al. treated four sacral GCT patients using only SAE with polymer microspheres. Three of four patients (75%) responded favorably, with improvement in pain and neurologic

Cryotherapy Cryotherapy in conjunction with intralesional resection has been reported in rare cases for treating GCTs [52–56]. Although more technically difficult due to the possibility of freezing neural tissue, Marcove et al. showed efficacy of treating sacral GCT using curettage or partial excision with adjunct cryotherapy. After gross tumor removal, the resulting cavity was treated with liquid nitrogen. Advantages included preservation of pelvic and spinal continuity, speed and ease of surgical procedure, and less blood loss. Four patients who presented with recurrent tumors after failing previous radiation treatment were treated with curettage and cryotherapy, and three patients were treated with limited excision and cryotherapy. At a median follow-up of 12.3 years (range, 2–14.2 years), all patients (100%) were disease-free. Local recurrence developed in two patients. Both of them underwent repeat curettage and cryotherapy and have since remained disease-free. Two patients had positive second-look biopsies that demonstrated microscopic tumor. Both of them were treated with repeat cryotherapy and have remained diseasefree. No patient suffered neurologic injury from cryotherapy [57]. Althausen et al. reported another case of a sacral GCT that was removed with an extensive intralesional resection, and cryotherapy was used to ablate the remaining tumor margin; 20 months after surgery, the patient was neurologically intact without tumor recurrence [58]. Schwimer et al. treated an SGCT in the odontoid base of C2 using transoral cryotherapy and 45 Gy of RT. Three years later, the patient remained tumor-free [59].

Argon beam coagulation Argon beam coagulation delivers radiofrequency energy to tissue across a jet of argon gas. Argon beam coagulation has been reported to be a useful adjuvant modality for local control of GCT in long bones resulting in low rates of local recurrence. Lewis et al. reported 37 long bone GCTs treated using ABC with curettage and cementation. Mean followup time was 74 months. The recurrence rate was only 8.3%, with a 5-year disease survival rate of 87.2% [60]. Takeda et al. reported cases of one lumbar vertebral GCT and one sacral GCT that were treated with ABC, curettage, and bone grafting. The patients had no local recurrence after 5 and 6 years’ follow-up, respectively [45].

266

P. Luksanapruksa et al. / The Spine Journal 16 (2016) 259–269

Medical treatment Bisphosphonates Bisphosphonates are antiresorptive drugs used in patients with myeloma and bone metastases to treat pain and reduce the risk of pathologic fractures. There is emerging evidence that bisphosphonates also have antitumoral effects as adjuvant therapy for GCT. Intravenous zolendronate has been used for local control after intralesional GCT excision [61]. Xu et al. administered one dose of zoledronic acid preoperatively and monthly doses postoperatively for 2 years to 37 SGCT patients. Compared with patients who did not receive bisphosphonate, these patients had significantly better recurrence-free survival (89% vs. 48%, p<.01) [12]. Gille et al. reported a case of cervical GCT treated with zoledronic acid and a rigid collar. After 36 months, clinical and radiological results revealed marked regression of the lesion [62]. Arpornchayanon and Leerapun also reported the effectiveness of intravenous bisphosphonate in treating SGCT. They administered 4 mg zoledronate intravenously every 4 weeks for seven courses followed with curettage and cement implantation in a single case of sacral GCT. At 2 years’ followup, the patient had no pain, no neurologic deficit, and no local recurrence [63]. Zhang et al. reported a case series of three patients with recurrent spinal GCTs who were treated with sodium ibandronate either postoperatively or upon recurrence of the tumor. After 2–6 years of follow-up, two patients had no recurrence, and the third patient had a recurrent sacral tumor that was well-controlled with sodium ibandronate [64]. Denosumab Denosumab is a monoclonal antibody that specifically binds receptor of activator nuclear factor kappa-B ligand (RANKL), thereby downregulating osteoclast activity. Denosumab has been shown to induce marked radiographic responses and to decrease pain in limb GCTs [65]. The FDA has approved denosumab for the treatment of unresectable GCTs, or when surgery is likely to result in severe morbidity [66]. Chawla et al. demonstrated that denosumab controlled surgically unresectable GCTs in 96% of patients; this cohort included 63 SGCT patients. Adverse events occurred in 9% of patients and included jaw osteonecrosis (1%), hypocalcemia (5%), and hypophosphatemia (3%) [67]. Thomas et al. treated 37 GCT patients with denosumab; 24 of these patients had recurrent disease. A positive treatment effect was seen in 86% of the patients within 6 months after beginning treatment [68]. Specific to the spine, Mattei et al. reported a 22-year-old female patient with a GCT of the C2 vertebral body and odontoid process who was treated with denosumab monotherapy. After 16 months, there was complete remission of the tumor and no side effects of denosumab. Computed tomography imaging revealed disappearance of osteolysis with new bone formation [69]. Goldschlager et al. conducted a multicenter, prospective series of five patients with GCT of the spine treated with denosumab. The result showed that all patients had a radiological response to denosumab. There was one patient

who failed to have histologic response (>90% of tumor cells found to be viable) [70]. However, Mak et al. reported that denosumab caused the absence of giant cells but persistence of stromal cells. Cell proliferation studies indicated that proliferation of stromal cells cultured from clinical specimens following denosumab treatment was approximately 50% slower than that of specimens from untreated patients. Thus, denosumab may only partially address the therapeutic needs of GCT patients, eliminating the giant cells but not destroying the neoplastic stromal cells [71]. The current experience shows that denosumab can control GCTs and potentially “harden up the edges” for those with extra-osseous extension to facilitate subsequent surgery. However, there is no defined endpoint for the use of denosumab as stand-alone treatment, and the current clinical experience has been for tumors to resume growth and activity when this is stopped. Interferon alpha-2b Interferon alpha-2b is an angiogenesis inhibitor that has been successfully used to treat GCT in long bones [72]. Wei et al. reported two cases of recurrent GCT of the mobile spine, after operative treatment at C1–C2 and sacral metastases after T5–T6 resection, retrospectively. Interferon alpha-2b at a dose of 3,000,000 U/m was then administered subcutaneously every day for 3–3.5 years. The C1–C2 lesion regressed steadily and was restricted and encircled within the lateral mass. Metastatic lesions in the lungs also significantly reduced. The pararectal lesions of the second patient disappeared completely. No major complications related to the use of interferon occurred [73]. Recurrent tumor management Because most data on GCTs come from relatively small series, there are wide ranges in reported recurrence rates for both long-bone GCTs (26–50%) [2,21,22,26] and SGCTs (17– 71%) [3,5,8,12,31,47]. Several studies have suggested that GCT recurrence is lower in the mobile spine than in the sacrum or extremities; however, given that each series used different surgical techniques and adjuvant therapies, this is difficult to state with certainty [8,23,74]. In a series of 24 SGCT patients, Hart et al. reported that SGCTs that included both the vertebral body and posterior elements had a higher likelihood of recurring than tumors in the vertebral body alone. Similarly, they found that extension into the spinal canal and paraspinal musculature predicted a higher recurrence rate, although this did not reach significance (odds ratio 2.45, p=.46) [2]. Larsson et al. also reported that GCTs extending into the soft tissues had a 34% higher chance of recurring than GCTs confined to the bone [21]. Ruggieri et al. reported overall survival after local recurrence of sacral GCT was 90% at both 60 and 120 months. Survival after local recurrence with and without radiation was 91% and 89%, with and without embolization was 91% and 86%, and with and without local adjuvants was 88% and 92% [39]. Xu et al. reported an overall 93% survival rate for SGCT.

P. Luksanapruksa et al. / The Spine Journal 16 (2016) 259–269

Options for managing recurrent GCTs include repeated surgical resection [34,75], combined radiotherapy and chemotherapy [76], and interferon alpha [73]. Surgical treatment for recurrent SGCT is more difficult than primary resections due to scarring and tumor extent, as well as the fact that many of these patients could not undergo total resection initially due to the difficulty presented by anatomic location. Yang et al. reoperated on five patients with recurrent SGCT, performing intralesional curettage (two patients), marginal excision (one patient), or wide excision (two patients). Postoperative RT was administered to the three patients with intralesional or marginal excisions. Both wide excision patients and one intralesional patient were alive without evidence of disease; of the other two patients, one experienced malignant transformation at the primary site, and the other developed lung metastases [19]. The overall behavior and treatment outcomes of GCT lung metastases are similar for extremity and spinal GCTs. Treatment options for these metastases consist of partial or complete lobectomy, chemotherapy, and RT [15]. For patients with pulmonary metastases who are poor surgical candidates, Feigenberg et al. recommended whole lung radiotherapy to 16 Gy with an additional boost to 35–45 Gy. This technique can also be used for patients who refuse thoracic surgery, whose disease is unresectable, or whose disease recurs or progresses after surgery or chemotherapy [77]. Secondary aneurysmal bone cysts can rarely arise from GCTs of the mobile spine, and have a more aggressive tendency to recur locally. Complete resection with systematic radiotherapy should be undertaken, which is associated with a good prognosis for local tumor control [78]. Treating SGCTs during pregnancy Cases of GCTs becoming symptomatic during pregnancy have been reported; the hormonal environment of pregnancy may contribute to rapid expansion of existing GCTs [1,79–81]. Pregnancy termination is typically not indicated, as GCTs are benign tumors in most cases. However, if tumor expansion causes vertebral collapse or neurologic deficit, then surgical intervention may be required. Because of the significant blood loss expected from surgery, operative treatment carries a high risk of fetal distress or harm [79]. Kathiresan et al. reported a case of a large thoracic spinal GCT presenting with spinal cord compression during pregnancy. The patient delivered a healthy girl by cesarean section at 38 weeks of gestation and underwent a T8–T9 laminectomy, posterior spinal decompression, and instrumented fusion. Two days later, she had a thoracotomy, corpectomy of the vertebral body, and anterior tumor debulking. The patient was discharged with improved lower extremity strength and recovered bowel and bladder function [80]. Meng et al. reported on 21 pregnant patients with spine tumors, 3 of whom had benign SGCTs and 2 of whom had malignant SGCTs. All patients had partial or complete paralysis caused by their tumors. The three patients with benign tumors underwent cesarean delivery in their

267

third trimester followed by surgery for tumor resection. The two patients with malignant SGCTs underwent therapeutic abortion (one patient in the first trimester and one in the second trimester) at the time of tumor resection [81]. In these difficult cases, extensive discussions with the patient and involvement of an obstetrics team in the decision process are vital. Summary Spinal giant cell tumors remain challenging tumors to treat, and evidence-based algorithms are lacking. When possible, preoperative arterial embolization, complete surgical removal with postoperative denosumab are the treatment of choice. However, because en bloc resection of these tumors is often very morbid, marginal resection or intralesional resection combined with numerous adjuvant therapies including cryotherapy and argon beam coagulation have been used. Denosumab, serial embolization, or RT are the choice of treatment in patients who present with unresectable tumor or who are at high risk for surgery. Spinal giant cell tumors during pregnancy are very rare, and pregnancy termination is usually not indicated. If tumor expansion causes vertebral collapse or neurologic deficit, then surgical intervention may be required unless there is a high risk of fetal distress. Spinal giant cell tumors should be approached on a case-by-case problem, as each presents unique challenges. Collaboration of spine surgeons, radiation oncologists, and medical oncologists is the best practice for creating the best treatment plans for these tumors. References [1] Orguc S, Arkun R. Primary tumors of the spine. Semin Musculoskelet Radiol 2014;18:280–99. [2] Hart RA, Boriani S, Biagini R, Currier B, Weinstein JN. A system for surgical staging and management of spine tumors. A clinical outcome study of giant cell tumors of the spine. Spine 1997;22:1773–82; discussion 83. [3] Sanjay BK, Sim FH, Unni KK, McLeod RA, Klassen RA. Giant-cell tumours of the spine. J Bone Joint Surg Br 1993;75: 148–54. [4] Wilartratsami S, Muangsomboon S, Benjarassameroj S, Phimolsarnti R, Chavasiri C, Luksanapruksa P. Prevalence of primary spinal tumors: 15-year data from Siriraj Hospital. J Med Assoc Thai 2014;97(Suppl. 9):S83–7. [5] Boriani S, Bandiera S, Casadei R, Boriani L, Donthineni R, Gasbarrini A, et al. Giant cell tumor of the mobile spine: a review of 49 cases. Spine 2012;37:E37–45. [6] Mendenhall WM, Zlotecki RA, Scarborough MT, Gibbs CP, Mendenhall NP. Giant cell tumor of bone. Am J Clin Oncol 2006;29:96–9. [7] Refai D, Dunn GP, Santiago P. Giant cell tumor of the thoracic spine: case report and review of the literature. Surg Neurol 2009;71:228–33; discussion 33. [8] Dahlin DC. Giant-cell tumor of vertebrae above the sacrum: a review of 31 cases. Cancer 1977;39:1350–6. [9] Larsson SE, Lorentzon R, Boquist L. Giant-cell tumors of the spine and sacrum causing neurological symptoms. Clin Orthop Relat Res 1975;111:201–11.

268

P. Luksanapruksa et al. / The Spine Journal 16 (2016) 259–269

[10] Junming M, Cheng Y, Dong C, Jianru X, Xinghai Y, Quan H, et al. Giant cell tumor of the cervical spine: a series of 22 cases and outcomes. Spine 2008;33:280–8. [11] Shimada Y, Hongo M, Miyakoshi N, Kasukawa Y, Ando S, Itoi E, et al. Giant cell tumor of fifth lumbar vertebrae: two case reports and review of the literature. Spine J 2007;7:499–505. [12] Xu W, Li X, Huang W, Wang Y, Han S, Chen S, et al. Factors affecting prognosis of patients with giant cell tumors of the mobile spine: retrospective analysis of 102 patients in a single center. Ann Surg Oncol 2013;20:804–10. [13] Feigenberg SJ, Marcus RB Jr, Zlotecki RA, Scarborough MT, Berrey BH, Enneking WF. Radiation therapy for giant cell tumors of bone. Clin Orthop Relat Res 2003;411:207–16. [14] Bsch D. Late pulmonary metastases of a giant-cell tumour of the spine. QJM 2012;105:1019. [15] Donthineni R, Boriani L, Ofluoglu O, Bandiera S. Metastatic behaviour of giant cell tumour of the spine. Int Orthop 2009;33:497–501. [16] Tubbs WS, Brown LR, Beabout JW, Rock MG, Unni KK. Benign giant-cell tumor of bone with pulmonary metastases: clinical findings and radiologic appearance of metastases in 13 cases. AJR Am J Roentgenol 1992;158:331–4. [17] Campanacci M, Baldini N, Boriani S, Sudanese A. Giant-cell tumor of bone. J Bone Joint Surg Am 1987;69:106–14. [18] Thakur NA, Daniels AH, Schiller J, Valdes MA, Czerwein JK, Schiller A, et al. Benign tumors of the spine. J Am Acad Orthop Surg 2012;20:715–24. [19] Yang SC, Chen LH, Fu TS, Lai PL, Niu CC, Chen WJ. Surgical treatment for giant cell tumor of the thoracolumbar spine. Chang Gung Med J 2006;29:71–8. [20] Si MJ, Wang CG, Wang CS, Du LJ, Ding XY, Zhang WB, et al. Giant cell tumours of the mobile spine: characteristic imaging features and differential diagnosis. Radiol Med (Torino) 2014;119:681–93. [21] Larsson SE, Lorentzon R, Boquist L. Giant-cell tumor of bone. A demographic, clinical, and histopathological study of all cases recorded in the Swedish Cancer Registry for the years 1958 through 1968. J Bone Joint Surg Am 1975;57:167–73. [22] Dahlin DC, Cupps RE, Johnson EW Jr. Giant-cell tumor: a study of 195 cases. Cancer 1970;25:1061–70. [23] Goldenberg RR, Campbell CJ, Bonfiglio M. Giant-cell tumor of bone. An analysis of two hundred and eighteen cases. J Bone Joint Surg Am 1970;52:619–64. [24] McCarthy EF. Giant-cell tumor of bone: an historical perspective. Clin Orthop Relat Res 1980;153:14–25. [25] Randall RL. Giant cell tumor of the sacrum. Neurosurg Focus 2003;15:E13. [26] McDonald DJ, Sim FH, McLeod RA, Dahlin DC. Giant-cell tumor of bone. J Bone Joint Surg Am 1986;68:235–42. [27] Martin C, McCarthy EF. Giant cell tumor of the sacrum and spine: series of 23 cases and a review of the literature. Iowa Orthop J 2010;30:69–75. [28] Fidler MW. Surgical treatment of giant cell tumours of the thoracic and lumbar spine: report of nine patients. Eur Spine J 2001;10:69–77. [29] Sharma RR, Mahapatra AK, Pawar SJ, Sousa J, Dev EJ. Craniospinal giant cell tumors: clinicoradiological analysis in a series of 11 cases. J Clin Neurosci 2002;9:41–50. [30] Leggon RE, Zlotecki R, Reith J, Scarborough MT. Giant cell tumor of the pelvis and sacrum: 17 cases and analysis of the literature. Clin Orthop Relat Res 2004;423:196–207. [31] Li G, Fu D, Chen K, Ma X, Sun M, Sun W, et al. Surgical strategy for the management of sacral giant cell tumors: a 32-case series. Spine J 2012;12:484–91. [32] Guo W, Ji T, Tang X, Yang Y. Outcome of conservative surgery for giant cell tumor of the sacrum. Spine 2009;34:1025–31. [33] Smitherman SM, Tatsui CE, Rao G, Walsh G, Rhines LD. Image-guided multilevel vertebral osteotomies for en bloc resection of giant cell tumor of the thoracic spine: case report and description of operative technique. Eur Spine J 2010;19:1021–8.

[34] Shoda N, Nakajima S, Seichi A, Kan A, Iwasaki M, Kitagawa T, et al. Computer-assisted anterior spinal surgery for a case of recurrent giant cell tumor. J Orthop Sci 2002;7:392–6. [35] Yamazaki M, Akazawa T, Okawa A, Koda M. Usefulness of threedimensional full-scale modeling of surgery for a giant cell tumor of the cervical spine. Spinal Cord 2007;45:250–3. [36] Samartzis D, Foster WC, Padgett D, Shen FH. Giant cell tumor of the lumbar spine: operative management via spondylectomy and shortsegment, 3-column reconstruction with pedicle recreation. Surg Neurol 2008;69:138–41; discussion 41-2. [37] Unal C, Eren GG, Isil E, Alponat A, Sarlak A. Utility of the omentum in sacral reconstruction following total sacrectomy due to recurrent and irradiated giant cell tumour of the spine. Indian J Plast Surg 2012;45:140–3. [38] Yamazaki T, McLoughlin GS, Patel S, Rhines LD, Fourney DR. Feasibility and safety of en bloc resection for primary spine tumors: a systematic review by the Spine Oncology Study Group. Spine 2009;34(22 Suppl.):S31–8. [39] Ruggieri P, Mavrogenis AF, Ussia G, Angelini A, Papagelopoulos PJ, Mercuri M. Recurrence after and complications associated with adjuvant treatments for sacral giant cell tumor. Clin Orthop Relat Res 2010;468:2954–61. [40] Khan DC, Malhotra S, Stevens RE, Steinfeld AD. Radiotherapy for the treatment of giant cell tumor of the spine: a report of six cases and review of the literature. Cancer Invest 1999;17:110–13. [41] Chakravarti A, Spiro IJ, Hug EB, Mankin HJ, Efird JT, Suit HD. Megavoltage radiation therapy for axial and inoperable giant-cell tumor of bone. J Bone Joint Surg Am 1999;81:1566–73. [42] Roeder F, Timke C, Zwicker F, Thieke C, Bischof M, Debus J, et al. Intensity modulated radiotherapy (IMRT) in benign giant cell tumors – a single institution case series and a short review of the literature. Radiat Oncol 2010;5:18. [43] Zhou M, Yang H, Chen K, Wang G, Lu J, Ji Y, et al. Surgical treatment of giant cell tumors of the sacrum and spine combined with preoperative transarterial embolization. Oncol Lett 2013;6:185–90. [44] Turcotte RE, Sim FH, Unni KK. Giant cell tumor of the sacrum. Clin Orthop Relat Res 1993;291:215–21. [45] Takeda N, Kobayashi T, Tandai S, Matsuno T, Shirado O, Watanabe T, et al. Treatment of giant cell tumors in the sacrum and spine with curettage and argon beam coagulator. J Orthop Sci 2009;14:210–14. [46] Ozaki T, Liljenqvist U, Halm H, Hillmann A, Gosheger G, Winkelmann W. Giant cell tumor of the spine. Clin Orthop Relat Res 2002;401:194– 201. [47] Ming Z, Kangwu C, Huilin Y, Genlin W, Jian L, Yiming J, et al. Analysis of risk factors for recurrence of giant cell tumor of the sacrum and mobile spine combined with preoperative embolization. Turk Neurosurg 2013;23:645–52. [48] Lin PP, Guzel VB, Moura MF, Wallace S, Benjamin RS, Weber KL, et al. Long-term follow-up of patients with giant cell tumor of the sacrum treated with selective arterial embolization. Cancer 2002;95:1317–25. [49] Hosalkar HS, Jones KJ, King JJ, Lackman RD. Serial arterial embolization for large sacral giant-cell tumors: mid- to long-term results. Spine 2007;32:1107–15. [50] Nakanishi K, Osuga K, Hori S, Hamada K, Hashimoto N, Araki N, et al. Transarterial embolization (TAE) of sacral giant cell Tumor (GCT) using spherical permanent embolic material superabsorbant polymer microsphere (SAP-MS). Springerplus 2013;2:666. [51] Finstein JL, Chin KR, Alvandi F, Lackman RD. Postembolization paralysis in a man with a thoracolumbar giant cell tumor. Clin Orthop Relat Res 2006;453:335–40. [52] Gouin F, Dumaine V, French S, Bone Tumor Study Groups G-G. Local recurrence after curettage treatment of giant cell tumors in peripheral bones: retrospective study by the GSF-GETO (French Sarcoma and Bone Tumor Study Groups). Orthop Traumatol Surg Res 2013;99(6 Suppl.):S313–18.

P. Luksanapruksa et al. / The Spine Journal 16 (2016) 259–269 [53] Jacobs PA, Clemency RE Jr. The closed cryosurgical treatment of giant cell tumor. Clin Orthop Relat Res 1985;192:149–58. [54] Lim YW, Tan MH. Treatment of benign giant cell tumours of bone in Singapore. Ann Acad Med Singapore 2005;34:235–7. [55] Malawer MM, Bickels J, Meller I, Buch RG, Henshaw RM, Kollender Y. Cryosurgery in the treatment of giant cell tumor. A long-term follow-up study. Clin Orthop Relat Res 1999;359:176–88. [56] Robinson D, Yassin M, Nevo Z. Cryotherapy of musculoskeletal tumors–from basic science to clinical results. Technol Cancer Res Treat 2004;3:371–5. [57] Marcove RC, Sheth DS, Brien EW, Huvos AG, Healey JH. Conservative surgery for giant cell tumors of the sacrum. The role of cryosurgery as a supplement to curettage and partial excision. Cancer 1994;74:1253–60. [58] Althausen PL, Schneider PD, Bold RJ, Gupta MC, Goodnight JE Jr, Khatri VP. Multimodality management of a giant cell tumor arising in the proximal sacrum: case report. Spine 2002;27:E361–5. [59] Schwimer SR, Bassett LW, Mancuso AA, Mirra JM, Dawson EG. Giant cell tumor of the cervicothoracic spine. AJR Am J Roentgenol 1981;136:63–7. [60] Lewis VO, Wei A, Mendoza T, Primus F, Peabody T, Simon MA. Argon beam coagulation as an adjuvant for local control of giant cell tumor. Clin Orthop Relat Res 2007;454:192–7. [61] Chaudhary P, Khadim H, Gajra A, Damron T, Shah C. Bisphosphonate therapy is effective in the treatment of sacral giant cell tumor. Onkologie 2011;34:702–4. [62] Gille O, Oliveira Bde A, Guerin P, Lepreux S, Richez C, Vital JM. Regression of giant cell tumor of the cervical spine with bisphosphonate as single therapy. Spine 2012;37:E396–9. [63] Arpornchayanon O, Leerapun T. Effectiveness of intravenous bisphosphonate in treatment of giant cell tumor: a case report and review of the literature. J Med Assoc Thai 2008;91:1609–12. [64] Zhang W, Zhang Y, Li P, Rhodesm SD, Wang Y, Xue X, et al. Administration of sodium ibandronate in the treatment of complicated giant cell tumor of the spine. Spine 2011;36:E1166–72. [65] Martin-Broto J, Cleeland CS, Glare PA, Engellau J, Skubitz KM, Blum RH, et al. Effects of denosumab on pain and analgesic use in giant cell tumor of bone: interim results from a phase II study. Acta Oncol 2014;53:1173–9. [66] Lewin J, Thomas D. Denosumab: a new treatment option for giant cell tumor of bone. Drugs Today 2013;49:693–700. [67] Chawla S, Henshaw R, Seeger L, Choy E, Blay JY, Ferrari S, et al. Safety and efficacy of denosumab for adults and skeletally mature adolescents with giant cell tumour of bone: interim analysis of an open-label, parallel-group, phase 2 study. Lancet Oncol 2013;14:901–8.

269

[68] Thomas D, Henshaw R, Skubitz K, Chawla S, Staddon A, Blay JY, et al. Denosumab in patients with giant-cell tumour of bone: an open-label, phase 2 study. Lancet Oncol 2010;11:275–80. [69] Mattei TA, Ramos E, Rehman AA, Shaw A, Patel SR, Mendel E. Sustained long-term complete regression of a giant cell tumor of the spine after treatment with denosumab. Spine J 2014;14: e15–21. [70] Goldschlager T, Dea N, Boyd M, Reynolds J, Patel S, Rhines LD, et al. Giant cell tumors of the spine: has denosumab changed the treatment paradigm? J Neurosurg Spine 2015;22:526–33. [71] Mak IW, Evaniew N, Popovic S, Tozer R, Ghert M. A translational study of the neoplastic cells of giant cell tumor of bone following neoadjuvant denosumab. J Bone Joint Surg Am 2014;96:e127. [72] Marler JJ, Rubin JB, Trede NS, Connors S, Grier H, Upton J, et al. Successful antiangiogenic therapy of giant cell angioblastoma with interferon alfa 2b: report of 2 cases. Pediatrics 2002;109:E37. [73] Wei F, Liu X, Liu Z, Jiang L, Dang G, Ma Q, et al. Interferon alfa-2b for recurrent and metastatic giant cell tumor of the spine: report of two cases. Spine 2010;35:E1418–22. [74] Di Lorenzo N, Spallone A, Nolletti A, Nardi P. Giant cell tumors of the spine: a clinical study of six cases, with emphasis on the radiological features, treatment, and follow-up. Neurosurgery 1980;6:29–34. [75] Matsumoto M, Ishii K, Takaishi H, Nakamura M, Morioka H, Chiba K, et al. Extensive total spondylectomy for recurrent giant cell tumor in the thoracic spine. Case report. J Neurosurg Spine 2007;6:600–5. [76] Shirzadi A, Drazin D, Bannykh S, Danielpour M. Giant cell tumor of the odontoid in an adolescent male: radiation, chemotherapy, and resection for recurrence with 10-year follow-up. J Neurosurg Pediatr 2011;8:367–71. [77] Feigenberg SJ, Marcus RB Jr, Zlotecki RA, Scarborough MT, Enneking WF. Whole-lung radiotherapy for giant cell tumors of bone with pulmonary metastases. Clin Orthop Relat Res 2002; 401:202–8. [78] Wu Z, Yang X, Xiao J, Feng D, Huang Q, Zheng W, et al. Aneurysmal bone cyst secondary to giant cell tumor of the mobile spine: a report of 11 cases. Spine 2011;36:E1385–90. [79] Ross AE, Bojescul JA, Kuklo TR. Giant cell tumor: a case report of recurrence during pregnancy. Spine 2005;30:E332–5. [80] Kathiresan AS, Johnson JN, Hood BJ, Montoya SP, Vanni S, Gonzalez-Quintero VH. Giant cell bone tumor of the thoracic spine presenting in late pregnancy. Obstet Gynecol 2011;118(2 pt 2): 428–31. [81] Meng T, Yin H, Li Z, Li B, Zhou W, Wang J, et al. Therapeutic strategy and outcome of spine tumors in pregnancy: a report of 21 cases and literature review. Spine 2015;40:E146–53.